Prevalence of Cardiovascular Events in Patients with Autosomal Dominant Polycystic Kidney DiseaseHelal I. · Reed B. · Mettler P. · Mc Fann K. · Tkachenko O. · Yan X.-D. · Schrier R.W.
Division of Renal Diseases and Hypertension, University of Colorado Denver, Aurora, Colo., USA Corresponding Author
Robert W. Schrier
University of Colorado Denver, Division of Renal Diseases and Hypertension
Box C-281, 1270 East 19th, RC2 7th floor, Room 7001
Aurora, CO 80045 (USA)
Background: This study evaluates the prevalence of cardiovascular events in autosomal dominant polycystic kidney disease (ADPKD) patients. Methods: We distributed surveys to 1,439 subjects from our ADPKD research database. In total, 426 subjects completed and returned surveys; 7 of these were from children and were excluded from the study. Results: The patients who responded were female (63.2%), nonHispanic (88.1%) and white (93.6%). The mean age of the total group was 53.2 ± 13.7 years; 82.8% had a family history of ADPKD and 32.5% had reached end-stage renal disease (ESRD). With respect to cardiovascular risk factors, 86.6% were hypertensive with a mean age at diagnosis of 36.9 ± 12.9 years and hypertension was significantly more prevalent in males. In addition, 19.6% of the subjects were obese, 20.8% were smokers, 8.7% had diabetes, 45.7% had high cholesterol and 17.8% were sedentary. The most prevalent self-reported cardiovascular events were arrhythmias (25.9%), evidence of peripheral vascular disease (16.5%), heart valve problems (14.4%), cardiac enlargement (9.5%), stroke or cerebral bleeding (7.5%), myocardial infarction (6%) and brain aneurysm (5.0%). The most commonly used antihypertensive medications were renin-angiotensin inhibitors used by 75% of ADPKD patients. Older ADPKD patients and those at ESRD had a significantly higher incidence of cardiovascular events. Conclusion: These findings support the high prevalence of cardiovascular risk factors and events in ADPKD patients which contribute to a greater mortality risk. Due to the prevalence of cardiovascular risk factors in the ADPKD population, early diagnosis and clinical intervention are recommended.
© 2012 S. Karger AG, Basel
Approximately 6 million Americans have chronic cardiovascular and kidney disease combined, resulting in an increasing epidemic of heart and kidney failure . This morbid association represents unique challenges to the clinician. Approximately 600,000 Americans are affected with autosomal dominant polycystic kidney disease (ADPKD), with over 2000 patients starting dialysis every year . Patients with ADPKD have an increased incidence of early onset hypertension, left ventricular hypertrophy (LVH) and cardiovascular abnormalities [3,4]. The reported relative mortality rate in patients with ADPKD ranges between 1.6-fold [95% confidence interval (CI) 1.3–2.0] and 3.2-fold higher (95% CI 2–4.8) in comparison to the general population .
Cardiovascular complications are the most common cause of morbidity and mortality in patients with ADPKD . Primary prevention is important to reduce early morbidity and mortality, thus the need for detection and treatment of cardiovascular risk factors in the ADPKD population. There is evidence that blockade of the renin-angiotensin-aldosterone system (RAAS) with better control of blood pressure has improved ADPKD patient and renal survival [7,8,9]. There also are results in hypertensive ADPKD patients which demonstrate that initial therapy with RAAS inhibition compared to diuretics necessitates significantly few antihypertensive medications for comparable control of blood pressure .
This study analyzed the cardiovascular events and risk factors in a large number of ADPKD patients according to gender, age, hypertension, cholesterol, smoking and end-stage renal disease (ESRD). This observational study was undertaken in an era in which the majority of patients were receiving RAAS inhibition.
We developed a 6-page survey that was distributed to 1,439 study subjects listed as having ADPKD in our database. The survey asked basic demographic questions and specific questions related to the occurrence of cardiovascular disease in ADPKD patients, including the occurrence of stroke, peripheral arterial disease, abdominal aortic aneurysm, angina pectoris, myocardial infarction, atrial or ventricular arrhythmias, LVH and cardiac valvular abnormalities. The survey also collected information regarding the presence and treatment of cardiovascular risk factors, including hyperlipidemia, smoking, diabetes mellitus, hypertension and medication use (see appendix).
The survey was sent in a single mailing (January 2011) with instructions and an envelope provided in which to return it. A total of 426 (30%) subjects with ADPKD returned the survey completed; of these, 7 were from patients under the age of 18 years and these were excluded from the analysis.
SAS version 9.3 PROC FREQ and PROC MEANS were used to obtain descriptive statistics for the surveys. The difference between the distribution of age categories for men and women was tested using a contingency table χ2 test. p < 0.05 was considered significant.
Proportions for demographics were calculated as a percentage of all respondents.Proportions for other tables were calculated as a percentage of those who responded to that question.
Because multiple outcomes were tested, p values were adjusted using the Bonferroni method. Adjusted p values less than 0.0036 (0.05/14) or unadjusted p values <0.05 were considered significant. This adjustment corrects for the probability of getting a significant p value purely by chance.
ADPKD patients who responded were female (63.2%), nonHispanic (88.1%) and white (93.6%) (table 1). The mean age of the total group was 53.2 ± 13.7 years; 82.8% had a family history of ADPKD and 32.5% had reached ESRD. Analysis of cardiovascular risk factors (table 2) demonstrated that 86.6% had hypertension with a mean age of diagnosis of 36.9 ± 12.9 years with a significantly higher prevalence in males. In addition, 19.6% were obese, 20.8% were smokers, 8.7% had diabetes, 45.7% had high cholesterol and 17.8% were sedentary. The most prevalent self-reported cardiovascular events (table 3) were arrhythmias (25.9%) with a mean age of diagnosis of 43.3 ± 16.4 years, evidence of peripheral vascular disease (16.5%; mean age of diagnosis 45 ± 13 years), heart valve problems (14.4%; mean age of diagnosis 41.2 ± 16.5 years), cardiac enlargement (9.5%; mean age of diagnosis 42.6 ± 13.9 years), stroke or cerebral bleeding (7.5%; mean age of diagnosis 50.8 ± 13.4 years), myocardial infarction (6%; mean age of diagnosis 53.4 ± 9.6 years) and brain aneurysm (5.0%; mean age of diagnosis 43.4 ± 13.7 years). Angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) were used in 75% of hypertensive ADPKD patients (table 4). Statins and antiplatelet medications (aspirin) were used in 11 and 22.5%, respectively.
Demographic parameters or cardiovascular risk factors were not significantly different between males and females (table 5). The occurrence of reported heart attacks was significantly higher in males (11.4%) than females (3.1%) (adjusted p value of 0.0136) (table 4).
ADPKD respondents over the age of 45 years were significantly more likely to report hypertension and high cholesterol than those 45 years or younger (table 6). Cardiovascular events were higher in older ADPKD respondents but did not reach significance (table 6).
ADPKD respondents with ESRD were significantly more likely to report diabetes, hypertension and high cholesterol levels (table 7). They also reported a significantly higher incidence of stroke or cerebral bleeding, heart attack and cardiac enlargement (table 7).
The most common extra-renal complications that contribute to morbidity and mortality in ADPKD patients are of a cardiovascular nature . Hypertension is the most frequent cardiovascular complication and contributes to both an increased incidence of cardiovascular mortality and a faster progression to ESRD [6,11,12]. Hypertension develops early in the course of ADPKD  and occurs in 50–70% of ADPKD patients with normal kidney function [14,15]. We previously reported a median age at diagnosis for hypertension in ADPKD of 32 years in males and 34 years in females . The current results support the presence of early hypertension in ADPKD. Hypertension is a widespread feature of this disease and has been reported in up to 80% of ADPKD patients with ESRD on dialysis . Thus, the main and most effective therapy in ADPKD remains control of hypertension primarily by including RAAS inhibition [7,8]. For the definitive answer of whether treatment with either ACEIs and/or ARBs results in a decreased rate of renal disease progression in ADPKD, we await the results of the HALT-PKD (Halt Progression of PKD) study . However, the control of hypertension in ADPKD patients is important as it is a specific risk factor for intracerebral hemorrhage and aneurysm ruptures .
Our study demonstrates a high prevalence of cardiovascular risk factors including hypertension, obesity, diabetes and hypercholesterolemia in an ADPKD population. In a previous study, 22% of ADPKD patients (age 35.9 ± 11.1 years) with normal kidney function also fulfilled the International Diabetes Federation criteria of metabolic syndrome .
LVH is a significant risk factor for cardiovascular morbidity and mortality and a common finding in hypertensive and even normotensive ADPKD patients [21,22,23,24]. However, a recent study in ADPKD patients with preserved renal function reported a prevalence of LVH of 3.9% . Increased LV mass index does occur in children and young adults with ADPKD [13,26,27,28]. The early onset of hypertension in ADPKD may be associated with LVH in nearly 50% of ADPKD patients by their 40s .Increased LV mass index has been found to be associated with poor renal and overall outcomes in ADPKD patients , and a significant correlation between hypertension and increased LV mass index has been demonstrated in both children and adult patients [13,26,27,28]. RAAS inhibition in hypertensive ADPKD patients has led to the long-term reversal of LVH [29,30]. This finding was significantly greater in association with a rigorous control of blood pressure (<120/80 mm Hg) in ADPKD patients .
Structural cardiac abnormalities are found more often in ADPKD patients than in non-ADPKD family members or in normal controls . A prospective echocardiographic study in ADPKD subjects found mitral valve prolapse in 26% and mitral regurgitation in 31% . Tricuspid regurgitation and aortic regurgitation were also found, in 15% and 8%, respectively . In our study, overall heart valve problems were found in 14.4% of patients.
The occurrence rate of coronary events, such as angina, myocardial infarction, and the need for coronary revascularization in ADPKD patients with normal renal function has not been previously reported in the literature. Our survey reported that 3.3% of respondents had angina, 6% had suffered a heart attack and 5.9% had undergone angioplasty, angioplasty and stent or cardiac valve surgery. The mean age for heart surgery was 50.7 ±11.9 years. ADPKD patients with ESRD had less coronary events than matched ESRD patients of other causes [32,33]. This has been attributed to less severe anemia in ADPKD patients [32,33], which is probably due to increased endogenous erythropoietin production .
Arterial aneurysms, particularly intracranial aneurysms, are more prevalent in ADPKD patients than in the general population (4.0–11.7 vs. 1.0%) [35,36]. Moreover, it has been suggested that ADPKD is a risk factor for coronary artery aneurysms . Abdominal aortic aneurysm also appears to be more prevalent in ADPKD patients [38,39,40], although in our cohort, the incidence was actually very low (0.8%). However, a tendency towards larger aortic diameters in ADPKD patients compared to a control population has previously been reported .
The other major vascular abnormality in ADPKD is intracranial aneurysms (ICA). The prevalence ranges from 5% in patients with no family history of ICA to 21% in those with a positive family history of ICA rupture [32,35,41]. The prevalence may be even higher in ADPKD patients on dialysis, as observed in our study. An occurrence rate of both asymptomatic and ruptured ICA of 33.3% has been reported in ADPKD patients with ESRD . Another study  found no difference in incidence of cerebrovascular accidents between ADPKD patients on dialysis and a non-PKD dialysis patient population. Only 25–50% of cerebrovascular accidents in ADPKD patients have been reported to result from ICA rupture [6,44]. In our cohort, brain aneurysm and stroke prevalence or intracerebral bleeding were 5 and 7.5%, respectively. ICA rupture accounts for a 35–55% risk of combined morbidity and mortality [19,45], so identification and screening of patients at risk for developing symptomatic ICA are recommended. Systematic screening of ICA with 3-dimensional magnetic resonance angiography (MRA) is recommended for ADPKD patients, particularly for adults (≥30 years), with a positive family history of hemorrhagic stroke or ICA, those undergoing major surgery with potential hemodynamic instability and those with high-risk occupations [46,47]. It has been recommended that MRA be conducted every 5 years if initially negative and every 2–3 years if positive . However, recent data support a requirement for less screening for ICAs in ADPKD patients and therefore widespread screening is not indicated .
Patients with non-PKD chronic kidney disease demonstrate significantly increased cardiovascular events and risk factors . However, ADPKD is unique, due to the early occurrence of hypertension, heart valve problems and ICA. As expected, older ADPKD patients and those with ESRD are at a higher risk for cardiovascular events; male gender, however, may be losing its importance as a risk factor. The early and effective treatment of hypertension in ADPKD is critical for the prevention of cardiovascular events in ADPKD.
There are intrinsic limitations to the survey-based nature of this study and the reported frequencies may be underestimated. Nevertheless, these findings confirm the high prevalence of cardiovascular risk factors and events in ADPKD patients which are associated with an increased risk for mortality. Moreover, older ADPKD subjects and those with ESRD had an increased risk for cardiovascular events, and this increased morbidity and mortality. Due to the prevalence and early onset of cardiovascular risk factors in the ADPKD population, early diagnosis and intervention by aggressively treating blood pressure in ADPKD patients is considered important for the prevention of LVH, cardiovascular complications and mortality.
I.H. received an International Society of Nephrology-funded fellowship and support from the Laboratory of Kidney Pathology (LR00SP01-Pr Ben Maiz Hedi), Charles Nicolle Hospital, Tunis, Tunisia.
P.M. was supported in part by NIH/NCRR Colorado CTSI, Grant No. UL1 RR025780.
The research was supported by grant Nos. M01RR00051, M01RR00069 General Research Centers Program, National Center for Research Resources (NCRR)/NIH, DK34039 from NIH(NIDDK) and by the Zell Family Foundation. The content of this publication are the authors sole responsibility and do not necessarily represent the official NIH views.
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Robert W. Schrier
University of Colorado Denver, Division of Renal Diseases and Hypertension
Box C-281, 1270 East 19th, RC2 7th floor, Room 7001
Aurora, CO 80045 (USA)
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